Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks that include deficits in learning and memory. Our data during the current funding period revealed a novel function of anandamide (AEA) and the cannabinoid type 1 receptor (CB1R) as a regulator of neurodegeneration (ND) in postnatal ethanol exposed neonatal (postnatal day 7, P7) mice that is associated with synaptic dysfunction in adult mice. In this application, we propose that postnatal ethanol exposure induces persistent enhancement of CB1R function to disrupt synaptic homeostasis and, learning and memory. Although prolonged exposure paradigms might align more closely to common etiologies of FASD, the binge model allows a more precise analysis of mechanisms and thus provides potential therapeutic targets for treatment. Our pilot data with postnatal ethanol models support that the enhanced CB1R activity observed in neonates persists through adulthood and that blocking CB1R long after postnatal ethanol exposure was able to rescue spatial memory deficits in adults. The overreaching objective of this renewal application is to better understand and define the molecular events responsible for the persistent expression of CB1R and its impact on development of the synaptic circuit, activity- dependent signaling, synaptic structure and neurobehavioral abnormalities observed in adult mice. The goal of Aim 1 is to test the hypothesis that postnatal ethanol exposure induces persistent expression of CB1R to adulthood and examine the histone and DNA modification at the CB1R promoter that support enhanced CB1R expression in neocortical and hippocampal structures. Specific Aim 2 will test the hypothesis that postnatal ethanol-induced persistent expression of CB1R disrupts development of the synaptic circuit and neuronal activity-dependent signaling events that might be involved in synaptic activity. Using both CB1R wild type and null mice, we will explore the extent to which the enhancement of CB1R is associated with the development of glutamatergic and GABAergic systems. We will evaluate the effect of enhanced CB1R function on activity-dependent signaling. Finally, Aim 3 will evaluate the hypothesis that postnatal ethanol induced neurobehavioral deficits can be attributed to persistent CB1R activity and can be rescued by blocking CB1R activity. We will evaluate long-term potentiation (LTP), ultrastructural changes in synapses using EM analysis, adult neurogenesis, social behavior, and learning and memory in adult mice treated with a CB1R antagonist from postnatal ethanol exposed adolescent mice. If successful, these data could open a new window into understanding of the mechanisms that might help develop potential therapeutic strategies for treating early ethanol-induced neurobehavioral abnormalities.